The present invention relates to a series of new heterocyclic compounds having tachykinin receptor antagonist activity. It also provides methods and compositions using them for therapeutic and prophylactic purposes, as well as processes for their preparation and intermediates used in their preparation.
The presence in the mammalian body of the various forms of tachykinin is associated with a variety of diseases and disorders, including respiratory diseases, such as asthma, bronchitis, rhinitis and coughs; allergies; ophthalmic inflammatory diseases, such as conjunctivitis and spring catarrh; dermal diseases, such as contact dermatitis, atopic dermatosis and urticaria; inflammatory diseases, such as rheumatism and arthrosis deformans; pain, such as migraine, headache and toothache; central nervous system diseases, such as anxiety and Alzheimer""s disease; and gastrointestinal diseases, such as colitis; and cystitis; and many others. Inhibition of the activity of these forms of tachykinin will, therefore, result in a new therapy and/or prophylaxis for these diseases and disorders.
The compounds of the present invention exhibit antagonism generally to tachykinin receptors, but especially to the receptors for substance P (which receptors are generally referred to as xe2x80x9cneurokinin 1 receptorsxe2x80x9d xe2x80x94NK1) and the receptors for neurokinin A (which receptors are generally referred to as xe2x80x9cneurokinin 2 receptorsxe2x80x9d xe2x80x94NK2). It is a particular advantage of the compounds of the present invention that they exhibit antagonism to both of these receptors, a so-called xe2x80x9cdual effectxe2x80x9d.
Compounds which are structurally close to those of the present invention are disclosed in FR 2729952, FR 2729953 and FR 2729954. However, these are selective for the NK1 receptors and none of these compounds exhibits the dual effects of the compounds of the present invention.
A few low molecular weight non-peptide compounds are known to exhibit antagonism to both of these receptors, for example some of the compounds disclosed in WO 9429309 (1994), WO 9417045 (1994), WO 9426735 (1994) and WO 9528389 (1995) exhibit such an effect. Typical examples of compounds which are disclosed in these documents are: 
However, oral absorption of these compounds is poor. As a result, these prior art compounds cannot be administered by mouth and must be administered parenterally, for example by injection. It is well known in the medical field that administration of any drug by injection is undesirable, as either the patient must be trained (and some patients are inherently untrainable) or the drug must be administered by experienced staff, which is expensive and inconvenient both for the patient and the staff.
There is, therefore, a need for a new tachykinin receptor antagonist which exhibits the aforementioned dual effects, and which has good oral absorption and a low toxicity.
We have now discovered a series of new compounds which exhibit an activity against the NK1 receptors which is at least equal to that of the prior art compounds showing a dual effect and which unexpectedly exhibit a much stronger activity against the NK2 receptors.
It is, therefore, an object of the present invention to provide a series of new heterocyclic compounds.
It is a further, and more specific, object of the present invention to provide such compounds which exhibit antagonism to tachykinin receptors.
It is a still further, and more specific, object of the present invention to provide such compounds which exhibit antagonism to those tachykinin receptors known as NK1 and NK2.
It is a still further, and more specific, object of the present invention to provide certain of such compounds which exhibit greatly improved activity.
Other objects and advantages of the present invention will become apparent as the description proceeds.
The compounds of the present invention are those compounds of formula (I): 
and the quaternary ammonium derivative thereof of formula (Ia): 
wherein:
R1 and R2 are the same as or different from each other, and each represents a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below;
A represents a methylene group, a carbonyl group or a sulfonyl group;
B represents a single bond between the groups represented by A and R1, an alkylene group having from 1 to 4 carbon atoms or an alkenylene group having from 2 to 4 carbon atoms;
D represents an oxygen or sulfur atom;
E represents an alkylene group having from 1 to 6 carbon atoms, a haloalkylene group having from 1 to 6 carbon atoms, a cycloalkane-1,1-diyl group having from 3 to 6 carbon atoms, a cycloalkane-1,1-diylmethyl group having from 3 to 6 carbon atoms in the cycloalkane part, or a cycloalkane-1,1-di(ylmethyl) group having from 3 to 6 carbon atoms in the cycloalkane part;
G represents an alkylene group having from 1 to 4 carbon atoms or an alkenylene group having from 2 to 4 carbon atoms;
L represents a group of formula xe2x80x94N(R3)xe2x80x94 or a group of formula xe2x80x94C(R4)(R5)xe2x80x94
wherein R3 represents a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below,
R4 represents a hydrogen atom, a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below, and
R5 represents a group of formula xe2x80x94COxe2x80x94R6, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an amino group, an acylamino group, an alkyl group which has from 1 to 6 carbon atoms and which is substituted by an acylamino group, an acylamino group whose nitrogen atom is substituted with an alkyl group having from 1 to 6 carbon atoms, a hydroxy group, a hydroxyalkyl group having from 1 to 6 carbon atoms, an alkoxyalkyl group in which the alkoxy and alkyl parts each has from 1 to 6 carbon atoms, or an aralkyloxyalkyl group having from 1 to 6 carbon atoms in the oxyalkyl part, and in which the aralkyl part is an alkyl group which has from 1 to 4 carbon atoms and which is substituted by from 1 to 3 carbocyclic aryl groups which are unsubstituted or which are substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below,
wherein R6 represents an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a group of formula xe2x80x94NRaRb, a carbocyclic aryl group or a heterocyclic group, said aryl group and said heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below
wherein Ra represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6 carbon atoms, an alkanesulfonyl group having from 1 to 6 carbon atoms, a haloalkanesulfonyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a carbocyclic aryl group which is unsubstituted or which is substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below, or an aralkyl group in which an alkyl group having from 1 to 4 carbon atoms is substituted by from 1 to 3 carbocyclic aryl groups as defined above, and
Rb represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6 carbon atoms, an alkanesulfonyl group having from 1 to 6 carbon atoms, a haloalkanesulfonyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 8 carbon atoms, a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below, or an aralkyl group in which an alkyl group having from 1 to 4 carbon atoms is substituted by from 1 to 3 carbocyclic aryl groups as defined above,
or
Ra and Rb together with the nitrogen atom to which they are attached represent a nitrogen-containing heterocyclic group,
or
R4 and R5 together with the carbon atom to which they are attached represent a cycloalkyl or heterocyclic group having from 5 to 10 ring atoms, said group being unsubstituted or being substituted by at least one substituent selected from the group consisting of substituents xcex2, defined below, and said heterocyclic group having a single hetero-atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, or R4 and R5 together with the carbon atom to which they are attached represent a cycloalkyl or heterocyclic group as defined above which is fused to a carbocyclic aryl group or an aromatic heterocyclic group, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined below;
R7 represents an alkyl group having from 1 to 6 carbon atoms; and
said substituents xcex1 are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 6 carbon atoms, haloalkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, aliphatic carboxylic acyl groups having from 1 to 6 carbon atoms, alkanesulfonyl groups having from 1 to 6 carbon atoms, haloalkanesulfonyl groups having from 1 to 6 carbon atoms, hydroxy groups, carboxy groups, alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkoxy part, acylamino groups having from 1 to 6 carbon atoms, alkanesulfonylamino groups having from 1 to 6 carbon atoms, haloalkanesulfonylamino groups having from 1 to 6 carbon atoms, amino groups, cyano groups, and alkylene groups having from 1 to 8 carbon atoms (to form a cycloalkyl group fused with the aryl or heterocyclic ring);
said substituents xcex2 are:
when substituting a carbon atom, oxo groups,
when substituting a nitrogen atom, selected from the group consisting of aliphatic acyl groups, alkanesulfonyl groups having from 1 to 6 carbon atoms, alkyl groups having from 1 to 6 carbon atoms which are unsubstituted or are substituted by at least one substituent preferably selected from the group consisting of substituents xcex3, defined below, carbocyclic aryl groups which are unsubstituted or are substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined above, and aralkyl groups in which an alkyl group having from 1 to 4 carbon atoms is substituted by from 1 to 3 carbocyclic aryl groups as defined above,
and, when substituting a sulfur atom, one or two oxygen atoms to form a sulfoxide or sulfone group; and
said substituents xcex3 are selected from the group consisting of halogen atoms, alkoxy groups having from 1 to 6 carbon atoms, aliphatic carboxylic acyl groups having from 1 to 6 carbon atoms, alkanesulfonyl groups having from 1 to 6 carbon atoms, haloalkanesulfonyl groups having from 1 to 6 carbon atoms, hydroxy groups, carboxy groups, alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkoxy part, acylamino groups having from 1 to 6 carbon atoms, amino groups, and cyano groups;
and pharmaceutically acceptable salts and esters thereof.
The invention also provides a composition for the treatment or prophylaxis of central nervous system diseases, neurodegenerative diseases, respiratory diseases, inflammatory diseases, allergies, hypersensitivity diseases, ophthalmological diseases, skin diseases, addictions, somatic diseases caused by stress, sympathetic reflex dystrophy, dysthymia, undesirable immune reactions, diseases relating to immunopotentiation, digestive diseases, emesis, urinary bladder functional diseases, eosinophilia, diseases caused by abnormal blood flow, and pain, which comprises an effective amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier or diluent.
The invention still further provides a method for the treatment or prophylaxis of a disease or disorder selected from the group consisting of central nervous system diseases, neurodegenerative diseases, respiratory diseases, inflammatory diseases, allergies, hypersensitivity diseases, ophthalmological diseases, skin diseases, addictions, somatic diseases caused by stress, sympathetic reflex dystrophy, dysthymia, undesirable immune reactions, diseases relating to immunopotentiation, digestive diseases, emesis, urinary bladder functional diseases, eosinophilia, diseases caused by abnormal blood flow, and pain, which comprises administering to an animal (which may be human) suffering from or susceptible to said disease or disorder an effective amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or ester thereof.
The invention also provides a compound of formula (Iz): 
wherein:
J represents an alkylene group having from 1 to 6 carbon atoms;
Ar represents a carbocyclic aryl group or aromatic heterocyclic group fused to the ring containing J and S, said aryl group and said aromatic heterocyclic group being unsubstituted or being substituted by at least one substituent preferably selected from the group consisting of substituents xcex1, defined above;
R14xe2x80x2 represents a hydrogen atom or an amino-protecting group; and
S*xe2x86x92O represents a sulfoxide group in which the sulfur atom is in the S-configuration.